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The risk of coronary thrombosis with cyclo-oxygenase-2 inhibitors does not vary with polymorphisms in two regions of the cyclo-oxygenase-2 gene.

ABSTRACT: AIMS: To investigate whether polymorphisms of the cyclo-oxygenase-2 (COX-2) gene modify the adverse cardiovascular effects of COX-2 inhibitors. METHODS: A case control study was conducted in the Hunter Region of New South Wales, Australia. Cases (n= 460) were hospitalized with acute coronary syndrome (ACS). Controls (n= 640) were recruited from the electoral rolls. Structured interviews gathered information on variables including recent ingestion of non-steroidal anti-inflammatory drugs (NSAIDs). Targeted genotyping of rs 20417(G > C) and rs5275 (T > C) polymorphisms was performed by real-time polymerase chain reaction using allele-specific probes. RESULTS: Ingestion of any NSAID in the week prior to interview was associated with an elevated risk for ACS: adjusted odds ratio 1.8 (1.2, 2.5). The rs 20417 and rs 5275 polymorphisms were not singly associated with risk for ACS: adjusted odds ratios 1.1 (0.80, 1.5) and 1.2 (0.88, 1.5), respectively. Individually, the polymorphisms did not modify the risk of ACS with the drugs. When analyses were conducted by haplotype, the adjusted odds ratio with celecoxib or rofecoxib in individuals who had one or two copies of the 'low risk' haplotype (no GT) was 1.2 (0.29, 5.0), compared with 2.1 (1.1, 4.0) with the 'high risk' haplotype (one or two copies of GT). CONCLUSIONS: We found little evidence of a gene/drug interaction. We found a statistically non-significant trend toward a lower risk of coronary events with NSAIDs in the presence of the 'low risk' haplotype. Even if confirmed, the clinical utility of the finding would be limited as this haplotype is carried by a minority of the population.

SUBMITTER: McGettigan P

PROVIDER: S-EPMC3195745 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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The risk of coronary thrombosis with cyclo-oxygenase-2 inhibitors does not vary with polymorphisms in two regions of the cyclo-oxygenase-2 gene.

McGettigan Patricia P Lincz Lisa F LF Attia John J McElduff Patrick P Bissett Linda L Peel Roseanne R Stokes Barrie B Hancock Stephen S Henderson Kim K Seldon Michael M Henry David D

British journal of clinical pharmacology 20111001 4

<h4>Aims</h4>To investigate whether polymorphisms of the cyclo-oxygenase-2 (COX-2) gene modify the adverse cardiovascular effects of COX-2 inhibitors.<h4>Methods</h4>A case control study was conducted in the Hunter Region of New South Wales, Australia. Cases (n= 460) were hospitalized with acute coronary syndrome (ACS). Controls (n= 640) were recruited from the electoral rolls. Structured interviews gathered information on variables including recent ingestion of non-steroidal anti-inflammatory d ...[more]

PMID: 21371074

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Project description:BackgroundDifferences between gastrointestinal and cardiovascular effects of traditional NSAID or cyclooxygenase-2 selective inhibitor (coxib) are affected by drug, dose, duration, outcome definition, and patient gastrointestinal and cardiovascular risk factors. We calculated the absolute risk for each effect.MethodsWe sought studies with large amounts of information to calculate annualised rates for clearly defined gastrointestinal (complicated upper gastrointestinal perforations, ulcers, or bleeds, but not symptomatic or endoscopic ulcers) and serious cardiovascular outcomes (antiplatelet trial collaborators - APTC - outcome of fatal or nonfatal myocardial infarction or stroke, or vascular death).ResultsMeta-analyses and large randomised trials specifically analysing serious gastrointestinal bleeding or cardiovascular events occurring with five different coxibs had appropriate data. In total there were 439 complicated upper gastrointestinal events in 49,006 patient years of exposure and 948 serious cardiovascular events in 99,400 patient years of exposure. Complicated gastrointestinal events occurred less frequently with coxibs than NSAIDs; serious cardiovascular events occurred at approximately equal rates. For each coxib, the reduction in complicated upper gastrointestinal events was numerically greater than any increase in APTC events. In the overall comparison, for every 1000 patients treated for a year with coxib rather than NSAID, there would be eight fewer complicated upper gastrointestinal events, but one more fatal or nonfatal heart attack or stroke. Three coxib-NSAID comparisons had sufficient numbers of events for individual comparisons. For every 1000 patients treated for a year with celecoxib rather than an NSAID there would be 12 fewer upper gastrointestinal complications, and two fewer fatal or nonfatal heart attacks or strokes. For rofecoxib there would be six fewer upper gastrointestinal complications, but three more fatal or nonfatal heart attacks or strokes. For lumiracoxib there would be eight fewer upper gastrointestinal complications, but one more fatal or nonfatal heart attack or stroke.ConclusionCalculating annualised event rates for gastrointestinal and cardiovascular harm shows that while complicated gastrointestinal events occur more frequently with NSAIDs than coxibs, serious cardiovascular events occur at approximately equal rates. For each coxib, the reduction in complicated upper gastrointestinal events was numerically greater than any increase in APTC events.

Project description:ObjectiveTo assess the effects of selective cyclo-oxygenase-2 (COX 2) inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of vascular events.DesignMeta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs.Data sourcesMedline and Embase (January 1966 to April 2005); Food and Drug Administration records; and data on file from Novartis, Pfizer, and Merck.Review methodsEligible studies were randomised trials that included a comparison of a selective COX 2 inhibitor versus placebo or a selective COX 2 inhibitor versus a traditional NSAID, of at least four weeks' duration, with information on serious vascular events (defined as myocardial infarction, stroke, or vascular death). Individual investigators and manufacturers provided information on the number of patients randomised, numbers of vascular events, and the person time of follow-up for each randomised group.ResultsIn placebo comparisons, allocation to a selective COX 2 inhibitor was associated with a 42% relative increase in the incidence of serious vascular events (1.2%/year v 0.9%/year; rate ratio 1.42, 95% confidence interval 1.13 to 1.78; P = 0.003), with no significant heterogeneity among the different selective COX 2 inhibitors. This was chiefly attributable to an increased risk of myocardial infarction (0.6%/year v 0.3%/year; 1.86, 1.33 to 2.59; P = 0.0003), with little apparent difference in other vascular outcomes. Among trials of at least one year's duration (mean 2.7 years), the rate ratio for vascular events was 1.45 (1.12 to 1.89; P = 0.005). Overall, the incidence of serious vascular events was similar between a selective COX 2 inhibitor and any traditional NSAID (1.0%/year v 0.9%/year; 1.16, 0.97 to 1.38; P = 0.1). However, statistical heterogeneity (P = 0.001) was found between trials of a selective COX 2 inhibitor versus naproxen (1.57, 1.21 to 2.03) and of a selective COX 2 inhibitor versus non-naproxen NSAIDs (0.88, 0.69 to 1.12). The summary rate ratio for vascular events, compared with placebo, was 0.92 (0.67 to 1.26) for naproxen, 1.51 (0.96 to 2.37) for ibuprofen, and 1.63 (1.12 to 2.37) for diclofenac.ConclusionsSelective COX 2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess.

Project description:BackgroundThe selectins play important roles in the inflammatory process of coronary artery disease (CAD) and myocardial infarction (MI). Previous studies have shown ambiguous findings regarding a possible association between the selectin genes and CAD. The E-selectin Ser128Arg polymorphism and the P-selectin Thr715Pro polymorphism have been investigated widely but with inconsistent results. We performed a comprehensive meta-analysis to shed light on this issue.MethodsData were extracted by searches of MEDLINE, Embase, CNKI, Wanfang, Google Scholar, PORTA, GeNii, CiNii, J-STAGE, Nurimedia and Koreanstudies Information Service System [Kiss] up to October 2013, in which 10 studies on the Ser128Arg polymorphism with 3369 cases and 2577 controls and 10 studies on the Thr715Pro polymorphism with 5886 cases and 18345 controls. A random-effects model was used to calculate the combined odds ratios. The between-study heterogeneity and publication bias were addressed.ResultsThe 128Arg carriers had a significant increased risk of CAD (allele comparison: P = 0.02, OR = 1.33, 95%CI 1.04-1.69, P(heterogeneity) = 0.01); The 715Pro conferred a non-significant risk reduction relative to the 715Thr (allele comparison: P = 0.40, OR = 0.94, 95%CI 0.82-1.08, P(heterogeneity) = 0.03).Subgroup analyses demonstrated that the 128Arg carriers had a significant increased risk of CAD among Asians (allele comparison: P = 0.001, OR = 2.07, 95%CI 1.33-3.24, P(heterogeneity) = 0.77) but not among Caucasians (allele comparison: P = 0.33, OR = 1.13, 95%CI 0.88-1.45, P(heterogeneity) = 0.08). Carrier status for the 715Pro was significantly associated with reduced risk of MI (allele comparison: P = 0.04, OR = 0.81, 95%CI 0.67-0.99, P(heterogeneity )= 0.14). The asymmetric funnel plot and the Egger's test (P = 0.041) suggested the presence of publication bias for the Ser128Arg polymorphism.ConclusionOur results suggested there is an increase in the risk of CAD conferred by the Ser128Arg polymorphism and the thr715Pro polymorphism may be a protective factor of MI.

Dataset Information

The risk of coronary thrombosis with cyclo-oxygenase-2 inhibitors does not vary with polymorphisms in two regions of the cyclo-oxygenase-2 gene.

Publications

The risk of coronary thrombosis with cyclo-oxygenase-2 inhibitors does not vary with polymorphisms in two regions of the cyclo-oxygenase-2 gene.

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